This invention relates to novel 5-substituted 1-(2'-deoxy-2'-substituted-.beta.-D-arabinofuranosyl)pyrimidine nucleosides which are useful as anti-viral and anti-cancer agents.
5-Bromo- and/or 5-iodo-2'-deoxycytidine inhibit the replication of herpes simplex virus (HSV) (Schildkraut et al, Mol. Pharmacol., 11, 153 (1975); Greer et al, Ann. N.Y. Acad. Sci., 255, 359 (1975)) as effectively as their corresponding deoxyuridine analogs. The deoxycytidine analogs are less toxic to uninfected cells than are 5-iodo (or 5-bromo)-2'-deoxyuridine apparently as a result of a virus-induced pyrimidine nucleoside kinase which converts the 5-halogenated deoxycytidines to the 5-halogenated deoxycytidylates and thence to the corresponding deoxyuridylates.
1-.beta.-D-Arabinofuranosylcytosine (ara-C), is a known anti-cancer agent (Talley et al, Cancer, 20, 809 (1967)) and also inhibits the multiplication of several DNA virus in cell culture (Buthala, Proc. Soc. Exptl. Biol. Med., 115, 69 (1964); Feldman, et al, ibid., 122, 243 (1966)). Therapeutic trials of ara-C in herpes infections were not encouraging because its therapeutic to toxic ratio approached unity (Lauter et al, Antimicrobial Agents Chemother., 6, 598 (1974)). Although 1-.beta.-D-arabinofuranosyluracil (ara-U) is devoid of anti-viral or anti-cancer activity, the 5-halogeno analogs show anti-viral activity (Underwood et al, Arch. Ophthamol., 72, 505 (1964)). Ara-T is active against HSV types 1 and 2 as well as against equine herpesvirus (Gentry et al, Virology, 65, 294 (1975); Aswell et al, Proc. Amer. Soc. Microbiol., 240 (1975)). 5-Methyl-ara-C is also active against herpesvirus infected cells in which deoxycytidine deaminase is present indicating that this nucleoside serves as an intracellular donor of ara-T that is phosphorylated to the nucleotide which then inhibits viral replication (Aswell et al, Ann. N.Y. Acad. Sci., 284, 342 (1977)). 5-Methyl-ara-C is devoid of anti-cancer activity. (Doerr et al, J. Med. Chem., 10, 247 (1967)). The 5-halogeno-ara-C derivatives have also shown anti-herpesvirus activity and are active against experimental herpes keratitis in rabbits (Renis et al, Antimicrobial Agents Chemotherap., 675 (1967)).